2.1 Immunodeficiency Diseases
Immunodeficiency diseases are generally classified into one of two categories; primary and secondary. Secondary immunodeficiency diseases occur as a result of an underlying disease. Typically, once the underlying disease is treated, the immunodeficiency is reversed. Primary immunodeficiency diseases occur in the absence of, or independently from, underlying diseases. Immunoglobulin deficiency syndromes, which occur due to defective B-cells or antibodies, account for about 50% of all primary immunodeficiencies.
X-linked agammaglobulinemia is an inherited disease. The defect is more frequently observed in males than in females. Mature B-cells are capable of making antibodies and developing “memory,” a feature in which the B-cell will rapidly recognize and respond to an infectious agent the next time it is encountered. All classes of antibodies are known to be decreased in agammaglobulinemia.
IgA deficiency is a disorder of the immune system characterized by increased susceptibility to infection. Patients with the disease fail to produce normal amounts of IgA. IgA provides the first line of defense for the inner surfaces of the body against infections of the lung, the intestine, the mouth, the urogenital tract and other areas lined by mucosal membranes. It is believed that IgA deficiency may result from the failure of B lymphocyte to mature into plasma cells that produce IgA antibodies. IgA deficiency is the most common disorder of the antibody system. Symptomatic patients suffer from recurrent and serious infections, including infections of the gastrointestinal tract, lungs, and sinuses, as well as allergic disorders, epilepsy, and cancer. There are currently no known therapies that address the underlying cause of IgA deficiency.
Transient hypo-gammaglobulinemia of infancy is a temporary disease of unknown cause. It is believed to be due to a defect in the development of T-helper cells, which recognize foreign antigens and activate T- and B-cells in an immune response. As the patient ages, the number and condition of T-helper cells may improve. Hypo-gammaglobulinemia is characterized by low levels of antibodies in the blood. During the disease period, patients have decreased levels of IgG and IgA antibodies that do not react well with infectious agents.
Common variable immunodeficiency (CVID) is a group of immunodeficiency syndromes in which B cell immunity is abnormal. Most patients have normal or near-normal numbers of circulating B cells, but the cells fail to differentiate into effective plasma B cells. As a result, patients have low or undetectable amounts of serum antibodies. The condition may result from insufficient stimulation of B cells rather than from a failure intrinsic to B cells. There are several thousand CVID patients in the U.S. and Europe, and CVID occurs equally in both genders. Most patients experience acute, recurring bacterial infections including pneumonia, bronchitis, and sinusitis. Current treatment involves regular administration of intravenous antibodies, which are prepared from pooled blood samples from thousands of individual donors.
Ig heavy chain deletions is a genetic disease in which part of the antibody molecule is not produced. It results in the loss of several antibody classes and subclasses, including most IgG antibodies and all IgA and IgE antibodies. It is believed that the disease occurs because part of the gene for the heavy chain has been lost.
Selective IgG subclass deficiencies are a group of genetic diseases in which some of the subclasses of IgG are not made. There are four subclasses in the IgG class of antibodies. As the B-cell matures, it can switch from one subclass to another. In these diseases, there is a defect in the maturation of the B-cells that results in a lack of switching.
IgG deficiency with hyper-IgM is a disease that results when the B-cell fails to switch from making IgM to IgG. This produces an increase in the amount of IgM antibodies present and a decrease in the amount of IgG antibodies. This disease is the result of a generic mutation.
Although various conventional therapies are currently being contemplated for immunodeficiency diseases, an ongoing need still exists for safe, effective and convenient therapies of these diseases.
2.2 IMiDS™
A number of studies have been conducted with the aim of providing compounds that can safely and effectively be used to treat diseases associated with abnormal production of TNF-α. See, e.g., Marriott, J. B., et al., Expert Opin. Biol. Ther. 1(4):1-8 (2001); G. W. Muller, et al., Journal of Medicinal Chemistry, 39(17): 3238-3240 (1996); and G. W. Muller, et al., Bioorganic & Medicinal Chemistry Letters, 8: 2669-2674 (1998). Some studies have focused on a group of compounds selected for their capacity to potently inhibit TNF-α production by LPS stimulated PBMC. L. G. Corral, et al., Ann. Rheum. Dis. 58:(Suppl 1) 1107-1113 (1999). These compounds, which are referred to as IMiDS™ (Celgene Corporation) or Immunomodulatory Drugs, show not only potent inhibition of TNF-α but also marked inhibition of LPS induced monocyte IL 13 and IL 12 production. LPS induced IL6 is also inhibited by immunomodulatory compounds, albeit partially. These compounds are potent stimulators of LPS induced IL10. Id. Particular examples of IMiD™s include, but are not limited to, the substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles described in U.S. Pat. Nos. 6,281,230 and 6,316,471, both to G. W. Muller, et al.